Fast soluble tablet

ABSTRACT

The object of the present invention is to provide a tablet that dissolves rapidly in the oral cavity (fast soluble tablets) that can be produced by a simple method without special preparation technology. The present invention is a fast soluble tablet which comprises two features: 1 the tablet base component is a sugar alcohol or the like, and 2 a kneaded mixture of a drug and a sugar alcohol or the like is subjected to compressive shaping prior to drying in the process when compressive shaped for preparing tablets by wet granulation. The fast soluble tablet of the present invention can be produced by a modification of the conventional tableting method, and possesses sufficient physico-chemical stability.

TECHNICAL FIELD

The present invention relates to a drug-containing fast soluble tabletthat dissolves rapidly in the oral cavity.

The fast soluble tablet usually dissolves in the oral cavity within 15seconds to 3 minutes, and is suitable for administration to infants, theaged, severely affected patients and others who have difficulty intaking tablets.

BACKGROUND ART

Oral dosage forms of drugs include tablets, granules, powders andliquids. Liquids, such as syrups, are suitable for administration to thephysically weakened aged and infants because they are easilyswallowable. However, they are not convenient because they must beaccurately weighed for each use. Another drawback is that the tendencyto deteriorate easily upon exposure to heat or atmosphere degrades thedrug's chemical and physical stability.

Granules and powders are free of the above drawbacks, but they are noteasily swallowable, and taking the accurate dose is difficult unlessthey are taken with water etc.

Tablets are suitable for administration of a certain accurate volumesand offers excellent chemical and physical stability for the drugcontained, but they have a drawback of difficult swallow for infants,the aged, severely affected patients and others. Overcoming the drawbackof poor swallowability would make it possible to provide an excellentpreparation free of the above-described drawbacks in other dosage forms.

As a solution to the problem of poor swallowability in tablets,freeze-dried preparations in a tablet form, based on a water-solublepolymer, have recently been developed (e.g., Japanese Patent UnexaminedPublication Nos. 44619/1978 and 86837/1991). They have overcome thedrawback of poor swallowability in tablets by causing the preparation todissolve rapidly in the oral cavity. However, they require a specialpreparation technology known as freeze-drying, resulting in drawbackssuch as difficulty in industrial mass-production, high production costand poor physical stability.

In recent years, tablets have been produced by subjecting tabletcomponents to compressive shaping under high pressure in a dry state.This is because tablets are essentially intended to be disintegrated inthe gastrointestinal tract to cause drug absorption and must bephysically and chemically stable from completion of tableting to reachto the gastrointestinal tract, so that the tablet components must bestrongly bound together by a compressive pressure. In early times, wettablets were available, which were molded and shaped into tablets whilein a wet state, followed by drying. However, such tablets were notrapidly soluble in the oral cavity because they were intended to bedisintegrated in the gastrointestinal tract. Also, as these tablets arenot strongly compressed mechanically and lack shape retention, they arenot practically applicable to modern use.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide a fast soluble tabletthat can be produced by a simple method without the above-describedspecial preparation technology known as freeze-drying.

Through intensive investigation, the present inventors found that theabove object could be accomplished by producing tablets based on apharmaceutical additive rapidly soluble in water by a modification ofthe conventional tableting method based on wet granulation and completedthe present invention.

A gist of the present invention is characterized by two features: 1) thetablet base component is a pharmaceutical additive rapidly soluble inwater, and 2) a kneaded mixture of a drug and a pharmaceutical additiverapidly soluble in water is subjected to compressive shaping while in awet state.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-4 show the relationship between tensile strength, oral cavity,dissolution time and compression force for the inventive tablets.

The present invention is hereinafter described in detail.

The pharmaceutical additive rapidly soluble in water may be anywater-soluble crystalline or powdery solid, exemplified by substances incommon use as excipients. It is preferable, however, that thepharmaceutical additive is a sweetening substance, since the fastsoluble tablet of the present invention dissolves rapidly in the oralcavity. Such substances include succharides such as sucrose, lactose,glucose and fructose, and sugar alcohols such as xylitol, sorbitol andmannitol.

Of the above-mentioned sugar alcohols, xylitol is preferred because ithas a good taste and dissolves most rapidly in the oral cavity. Mannitoland lactose are excellent in the compressive property described later,although they are inferior to xylitol in taste and dissolution rate.

In the present invention, these substances may be used in combination.Appropriate combination can offer only a combination of advantagesthereof.

The fast soluble tablet relating to the present invention is produced bysubjecting a kneaded mixture of a pharmaceutical additive rapidlysoluble in water as described above and a drug to compressive shapingbefore drying when compressive shaping is performed in the conventionaltableting method based on wet granulation. The present tablets aredifferent from conventional tablets in that the shaping and dryingoperations are reversed in order; conventional tablets are produced bymixing starting materials, adding a binder, kneading and drying themixture and subjecting the mixture to compressive shaping.

The compressive shaping pressure for shaping the fast soluble tabletrelating to the present invention may be relatively low, e.g., 50-1,000kg is sufficient. Although decreasing the pressure tends to yieldtablets of shorter oral cavity dissolution time, compressive shapingpressures lower than 50 kg result in formation of practicallyunapplicable tablets with insufficient tensile strength. Althoughincreasing the pressure tends to yield more tough tablets of improvedtensile strength, compressive shaping pressures exceeding 1,000 kgusually result in formation of tablets of longer oral cavity dissolutiontime. In some cases, however, tablets with practically acceptablestrength are obtained from an appropriate combination of two or more ofthe pharmaceutical additives, even when the compressive shaping pressureis lower than 50 kg. Also, in some cases tablets with shorter oralcavity dissolution time may be obtained from an appropriate combinationof two or more of the pharmaceutical additives, even when thecompressive shaping pressure exceeds 1,000 kg. Fast soluble tabletsproduced under a compressive shaping pressure out of the range of50-1,000 kg are therefore included in the scope of the presentinvention.

Tablets whose tensile strength exceeds 5 kg/cm² are practicallyapplicable. In some cases, however, tablets with even lower tensilestrength are practically applicable if they are packaged in suitableforms.

The mechanical strength of the fast soluble tablet relating to thepresent invention is retained mainly by the crosslinking force of thepharmaceutical additive rapidly soluble in water.

Conventional tablets are produced under compressive shaping pressures ofabout 500-3,000 kg.

When a sugar alcohol is applied in the present invention, e.g., xylitolis used alone, it is preferable that the compressive shaping pressure isabout 50-300 kg. Lower compressive shaping pressures make tablet shapingdifficult. Higher compressive shaping pressures result in formation ofpractically unapplicable tablets of insufficient tensile strength (seeFIG. 1).

When xylitol alone is used as a sugar alcohol, compressive shapingpressures exceeding 300 kg result in formation of tablets with decreasedtensile strength and increased oral cavity dissolution time. Whenxylitol is used in a mixture with lactose, mannitol or the like, tabletswith sufficiently high tensile strength and short oral cavitydissolution time can be obtained even when the compressive shapingpressure exceeds 300 kg.

For example, when xylitol is used in combination with lactose, tabletswith shorter oral cavity dissolution time and sufficient tensilestrength can be obtained by mixing them in a ratio of, for example, 8:2(see FIG. 2).

For example, when xylitol is used in combination with mannitol, tabletswith shorter oral cavity dissolution time and sufficient tensilestrength can be obtained by mixing them in a ratio of, for example, 8:2(see FIG. 3).

As mentioned above, when xylitol is used in a mixture with lactose ormannitol, better results are obtained than those obtained with xylitolalone. These results, however, have not been expected from the resultswith mannitol alone or lactose alone. This is because using mannitolalone or lactose alone results in considerably increased oral cavitydissolution time as well as increased tensile strength when thecompressive shaping pressure exceeds 300 kg (see FIG. 4).

The fast soluble tablet relating to the present invention ischaracterized by rapid dissolution in the oral cavity. For example, whenit is intended to incorporate a drug which may cause a problem, if usedas such, e.g., a drug which has a high bitterness, a masking treatmentsuch as microcapsulation or crystal surface coating is performed asappropriate, after which the drug is incorporated in the fast solubletablet of the present invention, result in elimination of such problem.

The kneaded mixture of a drug and a pharmaceutical additive rapidlysoluble in water is usually prepared by mixing the pharmaceuticaladditive rapidly soluble in water and the appropriately treated drug,adding and uniformly dispersing water, a binder solution or a saturatedsugar solution, and kneading. The amount of water added is preferablyabout 1-10% by weight, most preferably about 3% by weight, in the tabletcomposition before compressive shaping. Excess water results indissolution of sugar alcohol or sugar, or decreased shape retention,which in turn adversely affect the compressive shaping that follows andmake it difficult to dry the shaped product. Insufficient water resultsin tableting failures such as cracking at shaping, thus hamperingpreferred embodiment. The shaped tablet, even if obtained, lacksmechanical strength, and is fragile. The water added is preferablypurified water, for instance.

Compressive shaping can be achieved, irrespective of the form of thekneaded mixture, whether particulate, granular, soft lumpy or the like,as long as the kneaded mixture of the drug and the pharmaceuticaladditive rapidly soluble in water is wet. Compressive shaping machineswhich can be used include ordinary tableting machines, automaticcompressive shaping machines for Japanese cakes and lump sugar machines.

The fast soluble tablet relating to the present invention can beproduced more simply and in larger amounts, in comparison with theabove-described tableting method using freeze-drying technique, becausethey can be produced by a modification of the conventional tabletingmethod based on wet granulation compression, as stated above.

In the present invention, to further improve the physical properties ofthe preparation, known binders may be added in the process of thekneading operation. Although the binder for the present invention is notsubject to limitation, preference is given to substances of relativelyhigh dissolution rate. Such binders include polyvinylpyrrolidone (PVP),hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC)and the like. Acacia etc. may also be incorporated as appropriate.

The binder for the present invention may be contained at 0.1 to severalpercent by weight, preferably about 0.5-1% by weight, in the tabletcomposition before compressive shaping.

The fast soluble tablet relating to the present invention may be glazedby steam exposure for one to several seconds after compressive shapingand drying, to smooth the tablet surface for good appearance and preventabrasion of the tablet surface.

Any drug is applicable to the fast soluble tablet relating to thepresent invention, as long as it is orally administered. Such drugsinclude the following:

1. Antipyretic Analgesic Anti-inflammatory Agents

Indomethacin, aspirin, diclofenac sodium, ketoprofen, ibuprofen,mefenamic acid, dexamethasone, dexamethasone sodium sulfate,hydrocortisone, prednisolone, azulene, phenacetin, isopropylantipyrin,acetaminophen, benzydamine hydrochloride, phenylbutazone, flufenamicacid, mefenamic acid, sodium salicylate, choline salicylate, sasapyrine,clofezone, etodolac.

2. Antiulcer Agents

Sulpiride, cetraxate hydrochloride, gefarnate, irsogladine maleate,cimetidine, lanitidine hydrochloride, famotidine, nizatidine, roxatidineacetate hydrochloride.

3. Coronary Vasodilators

Nifedipine, isosorbide dinitrate, diltiazem hydrochloride, trapidil,dipyridamole, dilazep dihydrochloride, methyl2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate,verapamil, nicardipine, nicardipine hydrochloride, verapamilhydrochloride.

4. Peripheral Vasodilators

Ifenprodil tartrate, cinepazide maleate, cyclandelate, cinnarizine,pentoxyfyline.

5. Antibiotics

Ampicillin, amoxicillin, cefalexin, erythromycin ethylsuccinate,bacampicillin hydrochloride, minocycline hydrochloride, chloramphenicol,tetracycline, erythromycin.

6. Synthetic Antibacterial Agents

Nalidixic acid, piromidic acid, pipemidic acid trihydrate, enoxacin,cinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride,sulfamethoxazole trimethoprim, 6-fluoro-1-methyl-7-4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl!-4-oxo-4H1,3!thiazeto 3,2-a!quinoline-3-carboxylic acid.

7. Antispasmodics

Propantheline bromide, atropine sulfate, oxapium bromide, timepidiumbromide, butylscopolamine bromide, trospium chloride, butropium bromide,N-methylscopolamine methylsulfate, methyloctatropine bromide, butropiumbromide.

8. Antitussive, Anti-asthmatic Agents

Theophylline, aminophylline, methylephedrine hydrochloride, procaterolhydrochloride, trimetoquinol hydrochloride, codeine phosphate, sodiumcromoglicate, tranilast, dextromethorphane hydrobromide, dimemorfanphosphate, clobutinol hydrochloride, fominoben hydrochloride,benproperine phosphate, tipepidine hibenzate, eprazinone hydrochloride,clofedanol hydrochloride, ephedrine hydrochloride, noscapine,calbetapentane citrate, oxeladin tannate, isoaminile citrate.

9. Bronchodilators

Diprophylline, salbutamol sulfate, clorprenaline hydrochloride,formoterol fumarate, orciprenalin sulfate, pirbuterol hydrochloride,hexoprenaline sulfate, bitolterol mesylate, clenbuterol hydrochloride,terbutaline sulfate, mabuterol hydrochloride, fenoterol hydrobromide,methoxyphenamine hydrochloride.

10. Diuretics

Furosemide, acetazolarmide, trichlormethiazide, methyclothiazide,hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopenthiazide,spironolactone, triamterene, fluorothiazide, piretanide, metruside,ethacrynic acid, azosemide, clofenamide.

11. Muscle Relaxants

Chlorphenesin carbamate, tolperisone hydrochloride, eperisonehydrochloride, tizanidine hydrochloride, mephenesin, chlorozoxazone,phenprobamate, methocarbamol, chlormezanone, pridinol mesylate,afloqualone, baclofen, dantrolene sodium.

12. Brain Metabolism Improvers

Meclofenoxate hydrochloride.

13. Minor Tranquilizers

Oxazolam, diazepam, clotiazepam, medazepam, temazepam, fludiazepam,meprobamate, nitrazepam, chlordiazepoxide.

14. Major Tranquilizers

Sulpirid, clocapramine hydrochloride, zotepine, chlorpromazinon,haloperidol.

15. β-Blockers

Pindolol, propranolol hydrochloride, carteolol hydrochloride, metoprololtartrate, labetalol hydrochloride, acebutolol hydrochloride, butetololhydrochloride, alprenolol hydrochloride, arotinolol hydrochloride,oxprenolol hydrochloride, nadolol, bucumolol hydrochloride, indenololhydrochloride, timolol maleate, befunolol hydrochloride, bupranololhydrochloride.

16. Antiarrhythmic Agents

Procainamide hydrochloride, disopyramide, ajimaline, quinidine sulfate,aprindine hydrochloride, propafenone hydrochloride, mexiletinehydrochloride.

17. Gout Suppressants

Allopurinol, probenecid, colchicine, sulfinpyrazone, benzbromarone,bucolome.

18. Anticoagulants

Ticlopidine hydrochloride, dicumarol, warfarin potassium.

19. Antiepileptic Agents

Phenytoin, sodium valproate, metharbital, carbamazepine.

20. Antihistaminics

Chlorpheniramine maleate, cremastin fumarate, mequitazine, alimemazinetartrate, cycloheptazine hydrochloride.

21. Antiemetics

Difenidol hydrochloride, metoclopramide, domperidone, betahistinemesylate, trimebutine maleate.

22. Hypotensives

Dimethylaminoethyl reserpilinate dihydrochloride, rescinnamine,methyldopa, prazosin hydrochloride, bunazosin hydrochloride, clonidinehydrochloride, budralazine, urapidin.

23. Sympathomimetic Agents

Dihydroergotamine mesylate, isoproterenol hydrochloride, etilefrinehydrochloride.

24. Expectorants

Bromhexine hydrochloride, carbocysteine, ethyl cysteine hydrochloride,methyl cysteine hydrochloride.

25. Oral Antidiabetic Agents

Glibenclamide, tolbutamide, glymidine sodium.

26. Circulatory Agents

Ubidecarenone, ATP-2Na.

27. Iron Preparations

Ferrous sulfate, dried ferrous sulfate.

28. Vitamins

Vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, folic acid.

29. Pollakiuria Remedies

Flavoxate hydrochloride, oxybutynin hydrochloride, terodilinehydrochloride, 4-diethylamino-1,1-dimethyl-2-butynyl(±)-α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate.

30. Angiotensin-converting enzyme inhibitors

Enalapril maleate, alacepril, delapril hydrochloride.

EFFECTS OF THE INVENTION

The fast soluble tablet relating to the present invention has thefollowing effects:

(1) Offers improved compliance, including safe administration to theaged, children, infants and patients weak in swallowing ability.

(2) Free of the risk of suffocation due to a physical obstruction whenswallowed, thus offering improved safety.

(3) Safely administrable to patients on water intake restriction.

(4) Easily portable and suitable for transportation by patients.

(5) Free of the need of weighing, an essential drawback in liquids etc.

(6) Drug retention at high concentrations in tablets allows applicationto drugs that must be administered at high doses.

(7) Can be industrially produced more simply, more efficiently and inlarger amounts, in comparison with tableting based on freeze-drying.

BEST MODES FOR CARRYING OUT THE INVENTION

The present invention is hereinafter illustrated in more detail by meansof the following examples.

EXAMPLE 1

To 60 g of xylitol, 2 ml of purified water was added, followed bykneading in a mortar. 1 g of the kneaded mixture was subjected tocompressive shaping at a compression force of 100-700 kg and acompression rate of 20 mm/min, using a material testing machine(Autograph (trade mark):AG-5000, produced by Shimadzu Corporation), toyield tablets of 13 mm diameter. The resulting tablets were dried at 50°C. for 2 hours in a hot air circulation oven (GT-100, produced by AlpCorporation) to yield fast soluble tablets of the present invention.

EXAMPLE 2

48 g of xylitol and 12 g of lactose were uniformly mixed in a mortar,followed by kneading with 2 ml of purified water added. 1 g of thekneaded mixture was subjected to compressive shaping at a compressionforce of 100-700 kg and a compression rate of 20 mm/min, using amaterial testing machine (Autograph (trade mark):AG-5000, produced byShimadzu Corporation), to yield tablets of 13 mm diameter. The resultingtablets were dried at 50° C. for 2 hours in a hot air circulation oven(GT-100, produced by Alp Corporation) to yield fast soluble tablets ofthe present invention.

EXAMPLE 3

48 g of xylitol and 12 g of mannitol were uniformly mixed in a mortar,followed by kneading with 2 ml of purified water added. 1 g of thekneaded mixture was subjected to compressive shaping at a compressionforce of 100-700 kg and a compression rate of 20 mm/min, using amaterial testing machine (Autograph (trade mark):AG-5000, produced byShimadzu Corporation), to yield tablets of 13 mm diameter. The resultingtablets were dried at 50° C. for 2 hours in a hot air circulation oven(GT-100, produced by Alp Corporation) to yield fast soluble tablets ofthe present invention.

EXAMPLE 4

60 g of mannitol was placed in a mortar and kneaded with 2 ml ofpurified water. 1 g of the kneaded mixture was subjected to compressiveshaping at a compression force of 100-700 kg and a compression rate of20 mm/min, using a material testing machine (Autograph (trademark):AG-5000, produced by Shimadzu Corporation), to yield tablets of 13mm diameter. The resulting tablets were dried at 50° C. for 2 hours in ahot air circulation oven (GT-100, produced by Alp Corporation) to yieldfast soluble tablets of the present invention.

EXAMPLE 5

308 g of xylitol, 77 g of mannitol, 12.5 g of diclofenac sodium and 2.5g of polyvinylpyrrolidone were mixed in a kneader (KM-1.5, produced byKikusui Seisakusho, Ltd.) for 10 minutes, followed by kneading with 12ml of purified water added. The resulting mixture was applied to afeather mill (FM-1, produced by Hosokawa Micron Corp.) equipped with ascreen of 12 mm pores, to uniformize particle size. The resultinggranules were subjected to compressive shaping at a compression force of200 kg, using a tableting machine (Clean Press Correct 12HUK, producedby Kikusui Seisakusho, Ltd.) equipped with a forced mechanical stirrer,to yield tablets of 10.5 mm diameter weighing 800 mg each. The shapedtablets were then dried at 50° C. for 3 hours in a hot air circulationoven (GT-100, produced by Alp Corporation) to yield fast soluble tabletsof the present invention.

EXAMPLE 6

3 g of polyvinylpyrrolidone, 100 g of lactose and 3 g of oxybutyninhydrochloride were mixed in a micro-type through-vision mixer (W-8,produced by Tsutsui Rikagaku Kiki) for 8 minutes. 106 g of this mixtureand 394 g of xylitol were mixed in a kneader (KM-1.5, produced byKikusui Seisakusho, Ltd.) for 10 minutes, followed by kneading with 15ml of purified water added. The resulting mixture was applied to afeather mill (FM-1, produced by Hosokawa Micron Corp.) equipped with ascreen of 12 mm pores, to uniformize particle size. The resultinggranules were subjected to compressive shaping at a compression force of150 kg, using a tableting machine (Clean Press Correct 12HUK, producedby Kikusui Seisakusho, Ltd.) equipped with a forced mechanical stirrer,to yield tablets of 9 mm diameter weighing 500 mg each. The shapedtablets were then dried at 55° C. for 3 hours in a hot air circulationoven (GT-100, produced by Alp Corporation) to yield fast soluble tabletsof the present invention.

EXAMPLE 7

2.5 g of acacia powder, 146 g of mannitol and 10 g of nifedipine weremixed in a micro-type through-vision mixer (W-8, produced by TsutsuiRikagaku Kiki) for 8 minutes. 158.5 g of this mixture and 341.5 g ofxylitol were mixed in a kneader (KM-1.5, produced by Kikusui Seisakusho,Ltd.) for 10 minutes, followed by kneading with 14 ml of purified wateradded. The resulting mixture was applied to a feather mill (FM-1,produced by Hosokawa Micron Corp.) equipped with a screen of 12 mmpores, to uniformize particle size. The resulting granules weresubjected to compressive shaping at a compression force of 220 kg, usinga rotary tableting machine (RT-F-9, produced by Kikusui Seisakusho,Ltd.), to yield tablets of 15 mm diameter weighing 1,000 mg each. Theshaped tablets were then dried at 55° C. for 3 hours in a hot aircirculation oven (GT-100, produced by Alp Corporation) to yield fastsoluble tablets of the present invention.

EXAMPLE 8

1.5 g of polyvinylpyrrolidone, 412.5 g of xylitol, 111 g of lactose and125 g of cefalexin were mixed in a kneader (KM-1.5, produced by KikusuiSeisakusho, Ltd.) for 10 minutes, followed by kneading with 20 ml ofpurified water added. The resulting mixture was applied to a feathermill (FM-1, produced by Hosokawa Micron Corp.) equipped with a screen of12 mm pores, to uniformize particle size. The resulting granules weresubjected to compressive shaping at a compression force of 180 kg, usinga rotary tableting machine (RT-F-9, produced by Kikusui Seisakusho,Ltd.), to yield tablets of 15 mm diameter weighing 1,300 mg each. Theshaped tablets were then dried at 55° C. for 3 hours in a hot aircirculation oven (GT-100, produced by Alp Corporation) to yield fastsoluble tablets of the present invention.

Comparative Example 1

300 g of xylitol was passed through a 32-mesh sieve. 1 g of the powderwas subjected to compressive shaping at a compression force of 50-1,000kg and a compression rate of 20 mm/min, using a material testing machine(Autograph (trade mark):AG-5000, produced by Shimadzu Corporation), toyield tablets of 13 mm diameter for comparative testing.

Comparative Example 2

300 g of mannitol was passed through a 32-mesh sieve. 1 g of the powderwas subjected to compressive shaping at a compression force of 100-700kg and a compression rate of 20 mm/min, using a material testing machine(Autograph (trade mark):AG-5000, produced by Shimadzu Corporation), toyield tablets of 13 mm diameter for comparative testing.

Test Example 1

For the inventive fast soluble tablets of Example 1, the tablets ofComparative Example 1, and the undried tablets of Example 1, tensilestrength and oral cavity dissolution time were measured. Tensilestrength was measured using a material testing machine (Autograph (trademark):AG-5000, produced by Shimadzu Corporation) equipped with a 100 KGFload cell, at a compression rate of 20 mm/min, with a full scale of10-20 KGF. The point at which the load reduction rate for 1 secondlowerd to 50% of the full scale was taken as the breaking point. On thebasis of breaking point data, the tensile strength of each tabletpreparation was calculated as the mean of 5 tablets using the followingequation:

τ=2P/πDT

τ: Tensile strength (kg/cm²)

P: Hardness (kg)

D: Tablet diameter (cm)

T: Tablet thickness (cm)

Oral cavity dissolution time was measured as the mean of 5 subjects.Each tablet was kept unbitten in the mouth, and the time to tablet massdissolution and disappearance was measured. The results are given inFIG. 1.

From FIG. 1, it is seen that the fast soluble tablet of the presentinvention had excellent properties for a fast soluble tablet, having atensile strength exceeding 3 kg/cm² and an oral cavity dissolution timewithin 30 second when it was prepared under a compression force of50-300 kg. As for the undried tablets and the tablets obtained by drytableting, tensile strength was lower than 3 kg/cm² when they wereprepared under a compression force of 50-1,000 kg; they were notpractically applicable.

Test Example 2

For the inventive fast soluble tablets of Example 2, tensile strengthand oral cavity dissolution time were measured in the same manner as inTest Example 1. The results are given in FIG. 2.

From FIG. 2, it is seen that the fast soluble tablet of the presentinvention has excellent properties for a fast soluble tablet, having atensile strength exceeding 8 kg/cm² and an oral cavity dissolution timewithin 1 minute over the range of compression forces measured.

Test Example 3

For the inventive fast soluble tablets of Example 3, tensile strengthand oral cavity dissolution time were measured in the same manner as inTest Example 1. The results are given in FIG. 3.

From FIG. 3, it is seen that the fast soluble tablet of the presentinvention had excellent properties for a fast soluble tablet, having atensile strength exceeding 7 kg/cm² and an oral cavity dissolution timewithin 40 seconds over the range of compression forces measured.

Test Example 4

For the inventive fast soluble tablets of Example 4, the tablets ofComparative Example 2 and the undried tablets of Example 4, tensilestrength and oral cavity dissolution time were measured in the samemanner as in Test Example 1. The results are given in FIG. 4.

From FIG. 4, it is seen that the fast soluble tablet of the presentinvention were practically applicable, having much higher tensilestrength, in comparison with the undried tablets and the tabletsobtained by dry tableting.

Test Example 5

For the inventive fast soluble tablets of Examples 5 through 8, tensilestrength, oral cavity dissolution time, disintegration time and degreeof wear were measured. Tensile strength and oral cavity dissolution timewere measured in the same manner as in Test Example 1. Disintegrationtime was measured by the method using water specified in thePharmacopoeia of Japan. Friability was measured on one tablet for eachpreparation, using a friabilator. The results are given in Table 1.

                  TABLE 1                                                         ______________________________________                                               Example 5                                                                             Example 6 Example 7 Example 8                                  ______________________________________                                        Tensile  9.1       7.5       12.2    8.5                                      strength                                                                      (kg/cm.sup.2)                                                                 Dissolution                                                                            15        15        18      25                                       time                                                                          (in oral cavity,                                                              seconds)                                                                      Disintegration                                                                         12        12        15      20                                       time                                                                          (seconds)                                                                     Friability (%)                                                                         0.3       0.1       0.2     0.3                                      (in 3 minutes)                                                                Remarks  *Good     *Good     *Good   *Good                                             appearance                                                                              appearance                                                                              appearance                                                                            appearance                                        *Dissolved                                                                              *Dissolved                                                                              *Dissolved                                                                            *Dissolved                                        rapidly in                                                                              rapidly in                                                                              rapidly in                                                                            rapidly in                                        the oral  the oral  the oral                                                                              the oral                                          cavity.   cavity.   cavity. cavity.                                           *Easily   *Easily   *Easily *Easily                                           swallowable.                                                                            swallowable.                                                                            swallowable.                                                                          swallowable.                             ______________________________________                                    

From Table 1, it is seen that the fast soluble tablets of the presentinvention had excellent properties for a fast soluble tablet, having atensile strength exceeding 7 kg/cm² and an oral cavity dissolution timewithin 30 seconds.

FIG. 1 shows the relations between tensile strength, and oral cavitydissolution time and compression force for each of the inventive fastsoluble tablets of Example 1, the tablets of Comparative Example 1, andthe undried tablets of Example 1.

The abscissa indicates compression force; the left ordinate indicatestensile strength (kg/cm²); the right ordinate indicates oral cavitydissolution time (min).

In Figure, the symbols denote the following:

--▪--: Tensile strength of the inventive fast soluble tablets of Example1

--□--: Oral cavity dissolution time of the inventive fast solubletablets of Example 1

--▴--: Tensile strength of the undried tablets of Example 1

----: Tensile strength of the tablets of Comparative Example 1

FIG. 2 shows the relations between tensile strength, and oral cavitydissolution time and compression force for the inventive fast solubletablets of Example 2.

The abscissa indicates compression force; the left ordinate indicatestensile strength (kg/cm²); the right ordinate indicates oral cavitydissolution time (min).

In Figure, the symbols denote the following:

--▪--: Tensile strength of the inventive fast soluble tablets of Example2

--□--: Oral cavity dissolution time of the inventive fast solubletablets of Example 2

FIG. 3 shows the relations between tensile strength, and oral cavitydissolution time and compression force for the inventive fast solubletablets of Example 3.

The abscissa indicates compression force; the left ordinate indicatestensile strength (kg/cm²); the right ordinate indicates oral cavitydissolution time (min).

In Figure, the symbols denote the following:

--▪--: Tensile strength of the inventive fast soluble tablets of Example3

--□--: Oral cavity dissolution time of the inventive fast solubletablets of Example 3

FIG. 4 shows the relations between tensile strength, and oral cavitydissolution time and compression force for each of the inventive fastsoluble tablets of Example 4, the tablets of Comparative Example 2, andthe undried tablets of Example 4.

The abscissa indicates compression force; the left ordinate indicatestensile strength (kg/cm²); the right ordinate indicates oral cavitydissolution time (min).

In Figure, the symbols denote the following:

--▪--: Tensile strength of the inventive fast soluble tablets of Example4

--□--: Oral cavity dissolution time of the inventive fast solubletablets of Example 4

--▴--: Tensile strength of the undried tablets of Example 4

----: Tensile strength of the tablets of Comparative Example 2

What is claimed is:
 1. A rapidly soluble tablet for oral administration of a therapeutic substance to a human or animal which comprises a kneaded wet compressed shaped tablet which comprises an amount of xylitol and at least one member selected from the group consisting of lactose and mannitol sufficient to form a rapidly soluble tablet, in combination with a therapeutically effective amount of a therapeutic substance, said tablet having been compression shaped with a compression force of from about 50 to about 1000 kg in a wet state and thereafter dried, said wet tablet containing from about 1 to about 10% by weight of water.
 2. A tablet according to claim 1 wherein the additive is a water-soluble crystalline or powdery solid.
 3. A tablet according to claim 1 wherein the additive is a sweetening substance.
 4. A tablet according to claim 3 wherein the sweetening substance is a saccharide, a sugar alcohol or a mixture thereof.
 5. A tablet according to claim 1 wherein the additive is xylitol, manitol, lactose or a mixture of two or three thereof.
 6. A tablet according to claim 1 wherein the therapeutic substance is subjected to a masking treatment prior to combination with the additive.
 7. A tablet according to claim 1 which further comprises a binder.
 8. A tablet according to claim 7 wherein the binder is polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or acacia.
 9. A tablet according to claim 1 wherein the therapeutic substance is an antipyretic, an analgesic, an anti-inflammatory agent, an antiulcer agent, a coronary vasodilator, a peripheral vasodilator, an antibiotic, an antibacterial agent, an antispasmodic, an antitussive, an anti-asthmatic agent, a bronchodilator, a diuretic, a muscle relaxant, a brain metabolism improver, a tranquilizer, a β-blocker, an antiarrhythmic agent, a gout suppressant, an anticoagulant, an antiepileptic agent, an antihistaminic, an antiemetic, a hypotensive, a sympathomimetic agent, an expectorant, an oral antidiabetic agent, a circulatory agent, an iron preparation, a vitamin, a pollakiuria remedy, or an angiotensin-converting enzyme inhibitor.
 10. A process for the production of a rapidly soluble tablet for oral administration of a therapeutic substance to a human or animal which comprises mixing a pharmaceutical additive which is rapidly soluble in water and a therapeutically effective amount of a therapeutic substance, adding and uniformly dispersing an amount of water of from about 1 to about 10% by weight of the wet tablet and sufficient to enable the mixture to be kneaded, kneading the mixture and while the kneaded mixture is wet, compression shaping it with an automatic compressive cake shaping machine or a lump sugar machine at a compression force of about 50 to about 1000 kg into tablet form, and drying the tablet, whereby the tablets produced are rapidly soluble in the oral cavity of a human or animal upon administration.
 11. A process according to claim 10 wherein the amount of water is about 3 percent by weight.
 12. A process according to claim 10 which further comprises mixing a binder, of about 0.1 percent to about 2 percent by weight of the tablet before compression shaping, with the additive and the therapeutic substance.
 13. A process according to claim 7 wherein the binder is polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose or acacia.
 14. A process according to claim 10 wherein the therapeutic substance is subjected to a masking treatment prior to being mixed with the pharmaceutical additive.
 15. A process according to claim 12 wherein the amount of binder is from about 0.5 to about 1 percent by weight.
 16. A process according to claim 10 wherein the additive is a water-soluble crystalline or powdery solid.
 17. A process according to claim 10 wherein the additive is a sweetening substance.
 18. A process according to claim 17 wherein the sweetening substance is a saccharide, a sugar alcohol or a mixture thereof.
 19. A process according to claim 10 wherein the additive is xylitol, mannitol, lactose or a mixture of two or three thereof.
 20. A process according to claim 10 wherein the therapeutic substance is an antipyretic, an analgesic, an anti-inflammatory agent, an antiulcer agent, a coronary vasodilator, a peripheral vasodilator, an antibiotic, an antibacterial agent, an antispasmodic, an antitussive, an anti-asthmatic agent, a bronchodilator, a diuretic, a muscle relaxant, a brain metabolism improver, a tranquilizer, a β-blocker, an antiarrhythmic agent, a gout suppressant, an anticoagulant, an antiepileptic agent, an antihistaminic, an antiemetic, a hypotensive, a sympathomimetic agent, an expectorant, an oral antidiabetic agent, a circulatory agent, an iron preparation, a vitamin, a pollakiuria remedy, or an angiotensin-converting enzyme inhibitor.
 21. A rapidly soluble tablet made in accordance with the method of claim
 10. 22. A rapidly soluble tablet for oral administration of a therapeutic substance to a human or animal which comprises a kneaded wet compressed shaped tablet which comprises at least 93% by weight, based on the weight of the tablet, of a pharmaceutical additive which is rapidly soluble in water sufficient to form a rapidly soluble tablet and a therapeutically effective amount of a therapeutic substance, said tablet having been compression shaped with a compression force of from about 50 to about 1000 kg in a wet state and thereafter dried, said wet tablet containing from about 1 to about 3% by weight of water.
 23. A rapidly soluble tablet for oral administration of a therapeutic substance to a human or animal which comprises a kneaded wet compressed shaped tablet which comprises an amount of a pharmaceutical additive which is rapidly soluble in water sufficient to form a rapidly soluble tablet and a therapeutically effective amount of a therapeutic substance, said tablet having been compression shaped with a compression force of from about 150 to about 1000 kg in a wet state and thereafter dried, said wet tablet containing from about 1 to about 10% by weight of water.
 24. A process for the production of a rapidly soluble, glazed tablet for oral administration of a therapeutic substance to a human or animal, which comprises mixing a pharmaceutical additive which is rapidly soluble in water and a therapeutically effective amount of a therapeutic substance, adding and uniformly dispersing an amount of water of from about 1 to about 10% by weight of the wet tablet and sufficient to enable the mixture to be kneaded, kneading the mixture and while the kneaded mixture is wet, compression shaping it at a compression force of about 50 to about 1000 kg into tablet form, drying the tablet and glazing the outer surface thereof, whereby the tablets produced are rapidly soluble in the oral cavity of a human or animal upon administration.
 25. The process of claim 24, wherein said glazing is effected by exposing the tablet to steam for at least one second.
 26. A rapidly soluble tablet for oral administration of a therapeutic substance to a human or animal which comprises a kneaded wet compressed shaped tablet which comprises at least 93% by weight, based on the weight of the tablet, of a pharmaceutical additive which is rapidly soluble in water sufficient to form a rapidly soluble tablet and a therapeutically effective amount of a therapeutic substance, said tablet having been compression shaped with a compression force of from about 50 to about 1000 Kg in a wet state, with the wet tablet containing from about 1 to about 3% by weight of water, and thereafter drying the tablet and glazing the outer surface thereof, whereby the tablets produced are rapidly soluble in the oral cavity of a human or animal upon administration.
 27. The rapidly soluble tablet of claim 26, wherein said glazing is effected by exposing the tablet to steam for at least one second.
 28. The rapidly soluble tablet of claim 1, with said tablet having been compression shaped with a compression force of from about 150 to about 1000 kg in a wet state and thereafter dried. 